FoxG1 Interacts with Bmi1 to Regulate Self-Renewal and Tumorigenicity of Medulloblastoma Stem Cells§

Authors

  • Branavan Manoranjan,

    1. McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario, Canada
    2. Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
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  • Xin Wang,

    1. Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
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  • Robin M. Hallett,

    1. Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
    2. McMaster Centre for Functional Genomics, McMaster University, Hamilton, Ontario, Canada
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  • Chitra Venugopal,

    1. McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario, Canada
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  • Stephen C. Mack,

    1. Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
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  • Nicole McFarlane,

    1. McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario, Canada
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  • Sara M. Nolte,

    1. McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario, Canada
    2. Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
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  • Katrin Scheinemann,

    1. Department of Pediatrics, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada
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  • Thorsteinn Gunnarsson,

    1. Department of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada
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  • John A. Hassell,

    1. Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
    2. McMaster Centre for Functional Genomics, McMaster University, Hamilton, Ontario, Canada
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  • Michael D. Taylor,

    1. Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
    2. Department of Surgery, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
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  • Cathy Lee,

    1. Departments of Pediatrics, Experimental Medicine and Medical Genetics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada
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  • Joanna Triscott,

    1. Departments of Pediatrics, Experimental Medicine and Medical Genetics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada
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  • Colleen M. Foster,

    1. Departments of Pediatrics, Experimental Medicine and Medical Genetics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada
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  • Christopher Dunham,

    1. Department of Pathology & Laboratory Medicine, Division of Anatomic Pathology, BC Children's Hospital, Vancouver, British Columbia, Canada
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  • Cynthia Hawkins,

    1. Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
    2. Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
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  • Sandra E. Dunn,

    1. Departments of Pediatrics, Experimental Medicine and Medical Genetics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada
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  • Sheila K. Singh

    Corresponding author
    1. McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario, Canada
    2. Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
    3. Department of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada
    • Department of Surgery, McMaster Children's Hospital, McMaster Stem Cell & Cancer Research Institute, MDCL 5027, 1280 Main Street West, Hamilton, Ontario L8S 4K1, Canada
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    • Telephone: 905-521-2100, ext. 75237; Fax: 905-521-992


  • Author contributions: B.M.: conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing, and final approval of manuscript; X.W., R.M.H., and C.V.: conception and design, collection and/or assembly of data, and final approval of manuscript, S.C.M., N.M., S.M.N., C.L., J.T., C.M.F., and C.D.: collection and/or assembly of data and data analysis and interpretation, K.S., J.A.H., M.D.T., and C.H.: data analysis and interpretation; T.G.: provision of study material or patients; S.E.D.: conception and design, provision of study material or patients, collection and/or assembly of data, data analysis and interpretation, and final approval of manuscript, S.K.S.: conception and design, data analysis and interpretation, manuscript writing, and final approval of manuscript.

  • Disclosure of potential conflicts of interest is found at the end of this article.

  • §

    first published online in STEM CELLS EXPRESS April 17, 2013.

Abstract

Brain tumors represent the leading cause of childhood cancer mortality, of which medulloblastoma (MB) is the most frequent malignant tumor. Recent studies have demonstrated the presence of several MB molecular subgroups, each distinct in terms of prognosis and predicted therapeutic response. Groups 1 and 2 are characterized by relatively good clinical outcomes and activation of the Wnt and Shh pathways, respectively. In contrast, groups 3 and 4 (“non-Shh/Wnt MBs”) are distinguished by metastatic disease, poor patient outcome, and lack a molecular pathway phenotype. Current gene expression platforms have not detected brain tumor-initiating cell (BTIC) self-renewal genes in groups 3 and 4 MBs as BTICs typically comprise a minority of tumor cells and may therefore go undetected on bulk tumor analyses. Since increasing BTIC frequency has been associated with increasing tumor aggressiveness and poor patient outcome, we investigated the subgroup-specific gene expression profile of candidate stem cell genes within 251 primary human MBs from four nonoverlapping MB transcriptional databases (Amsterdam, Memphis, Toronto, Boston) and 74 NanoString-subgrouped MBs (Vancouver). We assessed the functional relevance of two genes, FoxG1 and Bmi1, which were significantly enriched in non-Shh/Wnt MBs and showed these genes to mediate MB stem cell self-renewal and tumor initiation in mice. We also identified their transcriptional regulation through reciprocal promoter occupancy in CD15+ MB stem cells. Our work demonstrates the application of stem cell data gathered from genomic platforms to guide functional BTIC assays, which may then be used to develop novel BTIC self-renewal mechanisms amenable to therapeutic targeting. STEM Cells2013;31:1266–1277

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